Dr. Topalian Named David Karnofsky Memorial Award Recipient for her contributions to the research of cancer

Dr. Topalian Named David Karnofsky Memorial Award Recipient for her contributions to the research of cancer –

Asco Daily News – Suzanne L. Topalian, MD, of Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, has been named the 2015 David A. Karnofsky Memorial Award and Lecture recipient for her outstanding contributions to the research, diagnosis, and treatment of cancer. Her research on programmed cell death 1 (PD-1) and its ligand PD-L1 has been instrumental in the development of anti–PD-1 agents for the treatment of advanced cancers. “I am honored to be receiving an award named after Dr. Karnofsky, who made so many basic observations and discoveries that are still relevant today,” Dr. Topalian said.

After obtaining her medical degree from Tufts University, Dr. Topalian began her training as a surgical oncologist. During her general surgical residency at Thomas Jefferson University, she had the opportunity to conduct a year-long research project in tumor immunology at the Children’s Hospital of Philadelphia. This experience led Dr. Topalian to change course.

“I became very enthusiastic about the potential of the immune system to eliminate cancer the same way that it eliminates viruses and bacteria, and the same way it rejects transplanted organs. It became obvious to me that all of the basic principles were really the same, and that it should be possible,” she said.

After completing her surgical residency, she joined the laboratory of Steven Rosenberg, MD, PhD, at the National Cancer Institute and continued tumor immunology research, eventually establishing her own laboratory. In 2006, she joined Johns Hopkins University as the inaugural director of the Melanoma Program in the Sidney Kimmel Comprehensive Cancer Center. She and her colleagues have developed a multidisciplinary program with an emphasis on clinical research.

Treatment of advanced melanoma has changed dramatically in the last several years—the culmination of many decades of basic laboratory research. A total of seven compounds have been recently approved by the U.S. Food and Drug Administration, including ipilimumab, vemurafenib, and peginterferon alfa-2b in 2011; dabrafenib and trametinib in 2013; and the anti–PD-1 agents pembrolizumab and nivolumab in 2014. Anti–PD-1 drugs are monoclonal antibodies that target PD-1, a protein that inhibits T-cell responses. Other drugs in development block PD-L1. Blocking the PD-1 pathway allows the immune system to recognize and attack cancer cells.

“For our field, [drug approvals] have really been a breakthrough, because prior to this we really didn’t have anything effective to offer our patients once their disease had progressed through first-line therapy,” she said.

Dr. Topalian’s laboratory has also developed an immunohistochemistry assay to detect expression of PD-L1 in tumor samples. This type of test may help determine if a patient is a good candidate for anti–PD-1 therapy, and it is now being tested prospectively in large clinical trials. Further development of predictive biomarkers may help investigators prioritize which types of cancer to test in clinical trials.

In addition to melanoma, early nivolumab clinical trials included patients with diverse cancer types: renal cell carcinoma, non–small cell lung cancer, colorectal carcinoma, and castration-resistant prostate cancer. When asked if there was anything that surprised her during the development of nivolumab, Dr. Topalian said that the effects seen in patients with lung cancer were unexpected. In an early study, a very transient tumor regression was seen in one patient with lung cancer.1 Although this finding did not qualify as a true response using standard criteria, it was enough to give the researchers pause. Additional patients with lung cancer who had not responded to previous treatments were enrolled in subsequent studies, and durable treatment responses were observed.2

“The responses seen in lung cancer catapulted anti–PD-1 drugs into a different category. We had not seen other kinds of immune therapies having an effect on lung cancer, and people had pretty much given up on immunotherapy for lung cancer because there had been so many things that didn’t work,” she said.

Understanding the full power and best use of these immunotherapeutic agents is an ongoing effort. In addition to phase III trials in melanoma, lung, and kidney cancers, these drugs are being investigated in bladder cancer, Hodgkin lymphoma, head and neck cancer, triple-negative breast cancer, colorectal cancers with a high level of microsatellite instability, and other tumor types. Preclinical findings suggest that combination therapies based on anti–PD-1 or anti–PD-L1 will be more powerful than monotherapy. Different combinations and sequences of treatments, therefore, need to be investigated in clinical trials to find the optimal treatment strategy. “There’s a flood of new information, and there are a lot of reasons to be very optimistic,” Dr. Topalian said.

References:

1. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167-3175.
2. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.